Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling

Endophytic fungi are proving to be an excellent source of chemical entities with unique structures and varied bioactivities. Terretonin (TE) and its structurally related derivatives are a class of meroterpenoids, possessing the same unique tetracyclic core skeleton, which have been reported from the...

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Autores principales:	Gamal A. Mohamed, Sabrin R. M. Ibrahim, Dina S. El-Agamy, Wael M. Elsaed, Alaa Sirwi, Hani Z. Asfour, Abdulrahman E. Koshak, Sameh S. Elhady
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>Aspergillus terreus</i> endophytic fungi terretonin anti-inflammatory LPS Nrf2 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/364d90e5ff4e44b4a1d82e37423e49b3
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spelling	oai:doaj.org-article:364d90e5ff4e44b4a1d82e37423e49b32021-11-25T16:48:16ZTerretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling10.3390/biology101112192079-7737https://doaj.org/article/364d90e5ff4e44b4a1d82e37423e49b32021-11-01T00:00:00Zhttps://www.mdpi.com/2079-7737/10/11/1219https://doaj.org/toc/2079-7737Endophytic fungi are proving to be an excellent source of chemical entities with unique structures and varied bioactivities. Terretonin (TE) and its structurally related derivatives are a class of meroterpenoids, possessing the same unique tetracyclic core skeleton, which have been reported from the <i>Aspergillus</i> genus. This study was carried out to assess the potential protective effects of TE separated from the endophytic fungus <i>A. terreus</i> against LPS (lipopolysaccharide)-induced ALI (acute lung injury) in mice. The results revealed that TE alleviated pulmonary edema as it lowered both the W/D lung ratio and protein content. The inflammatory response represented by inflammatory cell infiltration into the lung tissues was greatly repressed by TE. That was supported by the improved histopathological results and also by the reduced level of myeloperoxidase in the lung. TE showed a potent antioxidant activity as it attenuated lipid peroxidative markers (malondialdehyde, 4-hydroxynonenal, and protein carbonyl) and enhanced endogenous antioxidants (reduced glutathione, superoxide dismutase, and catalase) in lung tissues. Similarly, TE increased the mRNA expression of SIRT1, Nrf2, and its genes (<i>HO-1</i>, <i>NQO1</i>, and <i>GCLm</i>). On the other hand, TE restrained the activation of NF-κB (nuclear factor-κB) in the lung. Consequently, TE depressed the pro-inflammatory cytokines: nitric oxide (NOx), TNF-α (tumor necrosis factor-α), and interleukins (IL-6 and -1β). Additionally, TE inhibited NLRP3 signaling and interrupted apoptosis by decreasing the levels of proapoptotic markers (Bax and caspase-3) and increasing the level of an anti-apoptotic marker (Bcl-2). In conclusion, TE had a remarkable protective potential on LPS-induced lung damage via antioxidant and anti-inflammatory mechanisms. This finding encourages further investigations on this promising candidate.Gamal A. MohamedSabrin R. M. IbrahimDina S. El-AgamyWael M. ElsaedAlaa SirwiHani Z. AsfourAbdulrahman E. KoshakSameh S. ElhadyMDPI AGarticle<i>Aspergillus terreus</i>endophytic fungiterretoninanti-inflammatoryLPSNrf2Biology (General)QH301-705.5ENBiology, Vol 10, Iss 1219, p 1219 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>Aspergillus terreus</i> endophytic fungi terretonin anti-inflammatory LPS Nrf2 Biology (General) QH301-705.5
spellingShingle	<i>Aspergillus terreus</i> endophytic fungi terretonin anti-inflammatory LPS Nrf2 Biology (General) QH301-705.5 Gamal A. Mohamed Sabrin R. M. Ibrahim Dina S. El-Agamy Wael M. Elsaed Alaa Sirwi Hani Z. Asfour Abdulrahman E. Koshak Sameh S. Elhady Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling
description	Endophytic fungi are proving to be an excellent source of chemical entities with unique structures and varied bioactivities. Terretonin (TE) and its structurally related derivatives are a class of meroterpenoids, possessing the same unique tetracyclic core skeleton, which have been reported from the <i>Aspergillus</i> genus. This study was carried out to assess the potential protective effects of TE separated from the endophytic fungus <i>A. terreus</i> against LPS (lipopolysaccharide)-induced ALI (acute lung injury) in mice. The results revealed that TE alleviated pulmonary edema as it lowered both the W/D lung ratio and protein content. The inflammatory response represented by inflammatory cell infiltration into the lung tissues was greatly repressed by TE. That was supported by the improved histopathological results and also by the reduced level of myeloperoxidase in the lung. TE showed a potent antioxidant activity as it attenuated lipid peroxidative markers (malondialdehyde, 4-hydroxynonenal, and protein carbonyl) and enhanced endogenous antioxidants (reduced glutathione, superoxide dismutase, and catalase) in lung tissues. Similarly, TE increased the mRNA expression of SIRT1, Nrf2, and its genes (<i>HO-1</i>, <i>NQO1</i>, and <i>GCLm</i>). On the other hand, TE restrained the activation of NF-κB (nuclear factor-κB) in the lung. Consequently, TE depressed the pro-inflammatory cytokines: nitric oxide (NOx), TNF-α (tumor necrosis factor-α), and interleukins (IL-6 and -1β). Additionally, TE inhibited NLRP3 signaling and interrupted apoptosis by decreasing the levels of proapoptotic markers (Bax and caspase-3) and increasing the level of an anti-apoptotic marker (Bcl-2). In conclusion, TE had a remarkable protective potential on LPS-induced lung damage via antioxidant and anti-inflammatory mechanisms. This finding encourages further investigations on this promising candidate.
format	article
author	Gamal A. Mohamed Sabrin R. M. Ibrahim Dina S. El-Agamy Wael M. Elsaed Alaa Sirwi Hani Z. Asfour Abdulrahman E. Koshak Sameh S. Elhady
author_facet	Gamal A. Mohamed Sabrin R. M. Ibrahim Dina S. El-Agamy Wael M. Elsaed Alaa Sirwi Hani Z. Asfour Abdulrahman E. Koshak Sameh S. Elhady
author_sort	Gamal A. Mohamed
title	Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling
title_short	Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling
title_full	Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling
title_fullStr	Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling
title_full_unstemmed	Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling
title_sort	terretonin as a new protective agent against sepsis-induced acute lung injury: impact on sirt1/nrf2/nf-κbp65/nlrp3 signaling
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/364d90e5ff4e44b4a1d82e37423e49b3
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Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling

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